Synthesis of Water-Soluble (Aminoalkyl)camptothecin Analogues: Inhibition of Topoisomerase I and Antitumor Activity

William D. Kingsbury, Jeffrey C. Boehm, Dalia R. Jakas, Kenneth G. Holden, Gregory Gallagher, Mary Jo Caranfa, Francis L. McCabe, Leo F. Faucette, Randall K. Johnson, Robert P. Hertzberg, Sidney M. Hecht

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Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13,15,17,19,21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.

Original languageEnglish (US)
Pages (from-to)98-107
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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